title: Identification of 4-[1-[3-chloro-4-[N'-(5-fluoro-2-methylphenyl)ureido]phenylacetyl]-(4S)-fluoro-(2S)-pyrrolidinylmethoxy]benzoic acid as a potent, orally active VLA-4 antagonist.
abstract: Optimization of benzoic acid derivatives by introducing substituents into the diphenyl urea moiety led to the identification of compound 20l as a potent VLA-4 antagonist. Compound 20l inhibited eosinophil infiltration into bronchial alveolar lavage fluid in a murine asthma model by oral dosing and its efficacy was comparable to anti-mouse alpha4 antibody (R1-2). Furthermore, this compound significantly blocked bronchial hyper-responsiveness in the model.
authors.affiliation: Medicinal Chemistry Research Laboratories II, Daiichi Sankyo Co., Ltd, 1-16-13, Kitakasai, Edogawa-ku, Tokyo 134-8630, Japan. muro.fumihito.iy@daiichisankyo.co.jp
authors.forename: Fumihito
authors.initials: F
authors.lastname: Muro
authors.forename: Shin
authors.initials: S
authors.lastname: Iimura
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Yoneda
authors.forename: Jun
authors.initials: J
authors.lastname: Chiba
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Watanabe
authors.forename: Masaki
authors.initials: M
authors.lastname: Setoguchi
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Iigou
authors.forename: Gensuke
authors.initials: G
authors.lastname: Takayama
authors.forename: Mika
authors.initials: M
authors.lastname: Yokoyama
authors.forename: Tohru
authors.initials: T
authors.lastname: Takashi
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nakayama
authors.forename: Nobuo
authors.initials: N
authors.lastname: Machinaga
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001249:Asthma / Q000188:drug therapy; D001565:Benzoates / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004285:Dogs; D005260:Female; D020128:Inhibitory Concentration 50; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors*; D051379:Mice; D008807:Mice, Inbred BALB C; D010539:Permeability; D011758:Pyrroles / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D051381:Rats
chemical_list: C534076:4-(1-(3-chloro-4-(N'-(5-fluoro-2-methylphenyl)ureido)phenylacetyl)-(4S)-fluoro-(2S)-pyrrolidinylmethoxy)benzoic acid; D000893:Anti-Inflammatory Agents; D001565:Benzoates; D039041:Integrin alpha4beta1; D011758:Pyrroles